Breast cancer (BC) is one of the most prevalent malignant cancers affecting women globally. The risk factors for BC include, but are not limited to, hormonal status, ionizing radiation, obesity, and genetic factors (Smolarz, Nowak, and Romanowicz, 2022; Fan et al., 2014). According to statistical data from 2022, the global incidence of new breast cancer cases was estimated at approximately 2.309 million, making it the second most common cancer. Additionally, around 666,000 global breast cancer deaths placed it fourth in mortality rates, posing a substantial risk to the health of women worldwide (Bray et al., 2024). Common treatment modalities for BC include surgery, chemotherapy, radiotherapy, and hormone therapy. In recent years, targeted therapy and immunotherapy have contributed to longer survival rates for patients. However, patients undergoing these treatments may experience a high risk of adverse effects, including pain, cardiovascular disease, and diarrhea (Strijbos et al., 2024; García-Aranda and Redondo, 2019; Jerusalem, Lancellotti, and Kim, 2019), leading them to explore adjuvant therapeutic methods aimed at improving quality of life and reducing side effects. The application of plant bioactive substances in the treatment of breast cancer is increasingly gaining attention (Liang et al., 2019; Wang et al., 2020).

Plant bioactive substances can be derived from a variety of natural plants, including Green Tea, Red Clover, Boswellia serrata, and Cimicifuga racemosa, through advanced techniques such as ultrasound-assisted extraction, decoction extraction, and solvent extraction (Dostal et al., 2015; Ferraris et al., 2020; Wang et al., 2019; Valente et al., 2024). The therapeutic role of plant bioactive substances in breast cancer (BC) management has gained increasing prominence, primarily due to their ability to enhance treatment efficacy while mitigating the toxic side effects associated with conventional therapies in breast cancer patients (Wang et al., 2022; Valente et al., 2024). Research by J. Chen et al. demonstrated that Salvia miltiorrhiza effectively mitigated skin flap ischemia and prevented necrosis following mastectomy procedures (Chen et al., 2010). Furthermore, a study by Hamidian and colleagues revealed that prophylactic administration of ginseng supplementation may provide cardioprotective benefits against doxorubicin-induced early-onset cancer therapeutics-related cardiac dysfunction (CTRCD) and mitigate the decline in left ventricular ejection fraction (LVEF) in breast cancer patients undergoing treatment (Hamidian et al., 2023a). Additionally, research has suggested that isopropanolic black cohosh extract may prolong disease-free survival in breast cancer patients (Henneicke-von Zepelin et al., 2007).

However, most studies focus on the effects of individual plant bioactive substances on breast cancer (BC) patients without directly comparing different plant extracts (Brooker et al., 2006; Khosropanah et al., 2023; Kedzierska et al., 2012). The outcomes of various clinical studies exhibit significant heterogeneity, and there is a limited number of evidence-based medicine studies available in this area (Chung et al., 2015). Therefore, determining the optimal therapeutic approach within complex treatment regimens for BC patients is a critical clinical priority. Network Meta-Analysis (NMA) is an advanced statistical method that simultaneously compares the effects of multiple interventions, integrating both direct and indirect evidence to quantitatively evaluate and rank interventions within a complex treatment network (Chang et al., 2022; Shehab et al., 2025). In this article, we will use network meta-analysis to compare the therapeutic effects of different plant active substance in breast cancer patients, in order to provide effective evidence-based support for clinical decision-making.

This meta-analysis was rigorously conducted in accordance with the Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The research protocol has been formally registered with the PROSPERO registry under ID: CRD420251006422.

Two investigators independently reviewed the titles and abstracts of all documents, systematically excluding those that clearly did not meet the established inclusion criteria. Any discrepancies were resolved through discussion, and in cases of persistent disagreement, a third author was consulted for further evaluation to reach a consensus. The following data were recorded from the included randomized controlled trials (RCTs): (1) the first author; (2) publication year; (3) participant characteristics (e.g., sample size, age); (4) intervention measures; (5) statistical results, including the pooled effect estimates for each comparison across all outcomes.

A total of 13,650 articles were collected from electronic databases, supplemented by two additional articles obtained through manual searches. Following the removal of 1,239 duplicate articles using a reference management tool, the titles and abstracts of the remaining 12,413 articles were screened, resulting in the exclusion of 112,289 articles. The remaining 124 articles underwent a comprehensive review, resulting in the exclusion of 106 articles for reasons such as being non-randomized controlled trials, containing incomplete data or outcome measures, failing to meet inclusion criteria, or not adhering to the specified interventions of this review. Ultimately, 18 articles met the eligibility criteria and were included in the final analysis of the study (MacGregor et al., 2005; Tröger et al., 2014; Pelzer, Tröger, and Nat, 2018; Biswal et al., 2013; da Costa Miranda et al., 2009; Hasheminasab et al., 2020; Hamidian et al., 2023b; Saghatelyan et al., 2020; Mirzaei et al., 2022; Thamlikitkul et al., 2017; de Oliveira Campos et al., 2011; Chi et al., 2014; Semiglazov et al., 2006; Belcaro et al., 2018; Jafarimanesh et al., 2020; Noguchi, Maruyama, and Yamada, 2014; Semiglasov et al., 2004; Barton et al., 2013) (Figure 1).

All 18 articles included in the analysis were randomized controlled trials (RCTs). Among these, 10 were rated as having a low risk of bias, 8 as having a moderate risk, and none as having a high risk, suggesting that the overall quality of the studies was acceptable. Further details are presented in Figure 2, which provides a visual representation of the risk-of-bias assessment for the included RCTs.

This study analyzed 18 randomized controlled trials involving a total of 2,062 breast cancer patients. The control groups received various interventions, including soy capsules, peppermint extract, Viscum album [L.] extracts, Withania somnifera, Paullinia cupana, P. ovate husk, ginseng, curcumin, and chlorella extract. Among the studies, 11 used quality of life as an outcome measure, 10 assessed fatigue, 8 evaluated pain severity, 8 assessed physical functioning, 7 measured nausea, 7 reported role functioning, and 7 included emotional functioning as outcome measures (Table 2). A forest plot summarizing pooled effect sizes across outcomes to enhance visual interpretation, which has been included in the Supplementary Material (Supplementary Table S4).

This study evaluated the effects of several natural compounds on overall quality of life, mental health, and adverse reactions in individuals recovering from breast cancer. The analysis included 18 randomized controlled trials involving a substantial cohort of 2,062 breast cancer (BC) patients and examined the effects of fifteen distinct natural substances. The findings indicated that extracts from Withania somnifera were effective in enhancing quality of life, while also contributing to reductions in fatigue, pain, and nausea. Furthermore, Withania somnifera was associated with improvements in physical functioning, role functioning, and emotional functioning. In conclusion, the study underscores Withania somnifera as a beneficial natural option for reducing adverse reactions and improving mental health and overall quality of life in breast cancer patients.

This study demonstrates that Withania somnifera offers comparative benefits in enhancing quality of life compared to other plant-based substances. Withania somnifera (Indian ginseng or Ashwagandha) is a plant widely used in traditional medicine and is renowned for its diverse biological activities. Its active constituents, such as withaferin A and withanolides, are considered crucial to its pharmacological effects (Singh et al., 2021; Hassannia et al., 2020; Lem et al., 2022). These compounds have been shown to modulate various signaling pathways, including NF-κB, JAK-STAT, and AP-1, thereby reducing cancer-associated inflammation (White et al., 2016; Taniguchi and Karin, 2018). Furthermore, Withania somnifera improves reproductive system function by reducing infertility, enhancing spermatogenesis, and promoting sexual behavior in both male and female subjects (Nasimi Doost Azgomi et al., 2018). Studies have reported that Withania somnifera (WS) improves semen quality, enhances levels of vitamins E, C, and A, and promotes fertility. These beneficial effects are attributed to WS’s rich composition of alkaloids, ergostane steroids, and essential amino acids, which collectively enhance detoxification processes, reduce oxidative stress, and restore testosterone secretion (Ahmad et al., 2010). Withaferin A has been shown to mitigate oxidative stress by preserving the activity and levels of key antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, and the non-enzymatic antioxidant glutathione (GSH), while reducing thiobarbituric acid reactive species (TBARS). Catalase plays a critical role in cellular homeostasis by decomposing hydrogen peroxide (H₂O₂), and its deficiency or dysregulation is implicated in various age-related complication (Nandi et al., 2019). Furthermore, Withaferin A reduced myeloperoxidase (MPO) and nitrotyrosine levels and enhanced Nrf2 signaling in acute pancreatitis, highlighting its antioxidant role. Given that MPO elevation predicts diabetes and cardiovascular risk, MPO suppression could improve outcomes in aging patients (Giovannini et al., 2010).

Breast cancer patients often experience symptoms such as nausea, pain, and fatigue during their treatment (Qi et al., 2024; Zhang et al., 2022). Withania somnifera has shown promise in alleviating chemotherapy-induced fatigue and improving the quality of life for breast cancer patients (Biswal et al., 2013). Pro-inflammatory cytokines, such as IL-6 and IFN-γ, contribute to the promotion of neuropathic pain (Koch et al., 2007), whereas the inhibition of these cytokines or the administration of anti-inflammatory cytokines like IL-10 has been shown to alleviate neuropathic pain in animal models (Laumet et al., 2020; Kumar, Sharma, and Garg, 2022). In rat models, treatment with Withania somnifera root extract significantly reduced IFN-γ levels while increasing IL-10 expression following SNI-induced neuropathic pain. The analgesic effects of Withania somnifera (WS) against both postoperative and neuropathic pain appear to be mediated by its bioactive compounds, particularly withanolides (Lim et al., 2018; Orrù et al., 2014).

Breast cancer significantly impacts the mental and psychological health of patients, particularly during the initial diagnosis and the first year following treatment. Psychological distress is most pronounced during this period (Dinapoli et al., 2021; Fortin et al., 2021). Research indicates that Withania somnifera offers a range of potential benefits for mental and psychological health. The root extract of Withania somnifera, known as glycowithanolides, has demonstrated anxiolytic and antidepressant effects in rat models, supporting its potential use as a mood stabilizer (Pathak et al., 2021). Studies have found that Withania somnifera can be used to promote physical and mental health, restore vitality, and treat various central nervous system disorders, including epilepsy, stress, and neurodegenerative diseases (Kulkarni and Dhir, 2008). Clinical trials suggest that W. somnifera extract enhances cognitive function—including task performance, executive function, attention, and reaction time—in individuals with cognitive impairment, such as older adults with mild cognitive decline and those with schizophrenia, schizoaffective disorder, or bipolar disorder. Additionally, it demonstrates good tolerability, high adherence, and minimal side effects (Ng et al., 2020).

We conducted a statistical analysis of adverse events across the included 18 studies. The findings indicate that the plant extract is both safe and effective. The most frequently reported adverse reaction was injection and infusion site reactions. Other adverse events included mild to moderate nausea, febrile temperature, flatulence and gastritis, all of which resolved without sequelae (Supplementary Table S12).

Overall, our study has clinical implications. Withania somnifera has demonstrated superior efficacy in improving the overall quality of life, including physical and functional status, among breast cancer patients, while reducing side effects such as nausea, pain, and fatigue. Additionally, it has shown significant effects in enhancing mental wellbeing. These findings provide valuable insights for breast cancer patients considering plant-based active substances. However, the notably high effect sizes observed for Withania somnifera (e.g., SMD >5) warrant careful interpretation. While these estimates suggest a potent intervention effect, their clinical plausibility must be critically evaluated. It is important to consider whether these values may have been influenced by small-study effects, a common source of bias in meta-analyses wherein smaller studies tend to yield larger effect sizes. Future research with larger, rigorously designed trials is needed to validate these findings and clarify the true magnitude of the intervention’s benefit.

The results of the network meta-analysis (NMA) indicate that Withania somnifera is an effective natural product for improving the quality of life, reducing side effects, and promoting mental health in breast cancer patients. Therefore, we recommend the integration of Withania somnifera alongside standard treatment to enhance the overall quality of life in these patients. Our study provides valuable insights into the potential of plant-based active substances to improve quality of life, mitigate side effects, and support mental health in breast cancer patients. However, the limitations of the initial study design resulted in indirect comparisons for certain treatments, which may diminish the strength of the evidence presented. Consequently, there is a pressing need for more rigorous, high-quality randomized controlled trials to further validate the efficacy and safety of natural extracts in the treatment of breast cancer.